To test the hypothesis that tricyclic antidepressant use increases invasive female breast cancer incidence, we carried out a case-control study within the population of female beneficiaries of the Saskatchewan Prescription Drug Plan aged 35 years from 1981-995 with no history of cancer since 1970. This agency has provided full or partial coverage for outpatient prescriptions to Saskatchewan residents since 1975. We accrued 5882 histologically proven cases and 23,517 controls, randomly selected from the source population and individually matched on age and sampling time. Heavy exposure to any tricyclic antidepressants was associated with an elevated rate ratio for breast cancer 11-15 years later (2.02, 95% confidence interval: 1.34-3.04). Post hoc analyses based on the results of genotoxicity studies carried out using Drosophila melanogaster suggested that the increased risk could be attributed to the use of the six genotoxic tricyclic antidepressants, and not to the use of the four nongenotoxic tricyclic antidepressants. However, our results may have been confounded by the effects of other determinants of breast cancer associated with tricyclic antidepressant use.